Garduño-Tamayo Norma Angelica, Almazán Jorge Luis, Romo-Rodríguez Rubí, Valle-García David, Meza-Sosa Karla F, Pérez-Domínguez Martha, Pelayo Rosana, Pedraza-Alva Gustavo, Pérez-Martínez Leonor
Laboratorio de Neuroinmunobiología, Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnología, Universidad Nacional Autónoma de México (UNAM), Cuernavaca, Morelos, Mexico.
Laboratorio de Citómica del Cáncer Infantil, Centro de Investigación Biomédica de Oriente, Delegación Puebla, Puebla, Mexico.
J Neurosci Res. 2025 Feb;103(2):e70020. doi: 10.1002/jnr.70020.
Glial cells play a pivotal role in the Central Nervous System (CNS), constituting most brain cells. Gliogenesis, crucial in CNS development, occurs after neurogenesis. In the hypothalamus, glial progenitors first generate oligodendrocytes and later astrocytes. However, the precise molecular mechanisms governing the emergence of glial lineages in the developing hypothalamus remain incompletely understood. This study reveals the pivotal role of the transcription factor KLF10 in regulating the emergence of both astrocyte and oligodendrocyte lineages during embryonic hypothalamic development. Through transcriptomic and bioinformatic analyses, we identified novel KLF10 putative target genes, which play important roles in the differentiation of neurons, astrocytes, and oligodendrocytes. Notably, in the absence of KLF10, there is an increase in the oligodendrocyte population, while the astrocyte population decreases in the embryonic hypothalamus. Strikingly, this decline in the number of astrocytes persists into adulthood, indicating that the absence of KLF10 leads to an extended period of oligodendrocyte emergence while delaying the appearance of astrocytes. Our findings also unveil a novel signaling pathway for Klf10 gene expression regulation. We demonstrate that Klf10 is a target of CREB and that its expression is upregulated via the BDNF-p38-CREB pathway. Thus, we postulate that KLF10 is an integral part of the hypothalamic developmental program that ensures the correct timing for glial phenotypes' generation. Importantly, we propose that the Klf10 mouse model represents a valuable tool for investigating the impact of reduced astrocyte and microglia populations in the homeostasis of the adult hypothalamus.
神经胶质细胞在中枢神经系统（CNS）中起着关键作用，构成了大多数脑细胞。神经胶质细胞生成在中枢神经系统发育中至关重要，发生在神经发生之后。在下丘脑中，神经胶质祖细胞首先产生少突胶质细胞，随后产生星形胶质细胞。然而，发育中的下丘脑神经胶质谱系出现的精确分子机制仍未完全了解。本研究揭示了转录因子KLF10在胚胎下丘脑发育过程中调节星形胶质细胞和少突胶质细胞谱系出现方面的关键作用。通过转录组学和生物信息学分析，我们鉴定了新的KLF10假定靶基因，这些基因在神经元、星形胶质细胞和少突胶质细胞的分化中起重要作用。值得注意的是，在缺乏KLF10的情况下，胚胎下丘脑中少突胶质细胞数量增加，而星形胶质细胞数量减少。令人惊讶的是，星形胶质细胞数量的这种下降持续到成年期，表明缺乏KLF10会导致少突胶质细胞出现的时间延长，同时延迟星形胶质细胞的出现。我们的研究结果还揭示了Klf10基因表达调控的一条新信号通路。我们证明Klf10是CREB的靶标，其表达通过BDNF-p38-CREB途径上调。因此，我们推测KLF10是下丘脑发育程序的一个组成部分，可确保神经胶质表型产生的正确时间。重要的是，我们提出Klf10小鼠模型是研究成年下丘脑稳态中星形胶质细胞和小胶质细胞数量减少影响的有价值工具。
